The overall objective of this project is to obtain detailed information on the biochemical aspects of ischemia (acute and subacute) and the various stages of hypertrophy, including the transition to failure. In both pathological cases the function and structure of the sarcoplasmic reticulum and the regulatory proteins will be investigated. In hypertrophied hearts detailed studies on various aspects of the myosin molecule will be carried out in order to settle the question of the presence of a new myosin isozyme and any changes in its structure. Functionally important regions of fragments resulting from limited proteolytic digestion of myosin will be identified and located with the use of radioactive labels. Attempts will be made to explain the observed differences in the ATPase activities of myosins from normal and hypertrophied (thyroxine treatment or surgical intervention) myosins by comparing their structural differences. These studies will produce information relevant to the molecular mechanism of the pathogenesis of ischemia and hypertrophy of the heart.